Maillard in 1912 found that reducing sugars, such as glucose and ribose react with proteins to form brown pigments. Further studies have shown that this is an irreversible non-enzymatic reaction, which occurs in several natural systems including stored foodstuff. The Maillard reaction occurs in two stages, early and advanced. Initially, proteins react with glucose to form stable Amadori products, which subsequently cross-links to form advanced glycation end products (AGE). In most cases, the formation of AGE also accompanies browning of the proteins and increase in the fluorescence.
In diabetes, where blood glucose level is significantly higher than normal, the reaction of glucose with several proteins such as hemoglobin and collagen, gives rise to the formation of AGE, which in turn, is responsible for the complications associated with diabetes, such as nephropathy, microangiopathy, endothelial dysfunction and other organ dysfunctions. In addition, the activity of several growth factors, such as basic fibroblast growth factor, is also impaired. AGE products, unlike normal proteins in tissue, have a slower rate of turnover and replenishment. It has been reported that AGE products may in fact elicit a complex immunological reaction involving RAGE (Receptor for Advanced Glycation End Products) and activation of several incompletely defined immunological processes. (Stehouwer et al; Cardiovascular Research 1997; 34:55-68 and Smit et al; Current Medicinal Chemistry 2004; 11:2767-84).
Due to the clinical significance of AGE formation, several successful therapeutic approaches have been tried based upon intervening in the accumulation of AGEs in vivo. One of the approaches is to inhibit the formation of AGEs from its precursors, by the administration of therapeutic agents. In another approach for controlling levels of AGEs in tissues, therapeutic agent is administered which can reverse or break AGE cross-links, especially in those tissues in which AGE cross-links have already accumulated to levels which are responsible for subclinical or clinical pathology.
1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium and its pharmaceutically acceptable salts is one of a class of compounds which have been shown to have AGE breaking activity (EP1222171; EP1243581).
1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium chloride has been shown to improve cardiomyopathy and nephropathy in animal models of Type II diabetes (Joshi et al; J. Cardiovasc. Pharmacol.; 2009, 54(1): 72-81). Clinical studies have shown this compound to be safe and well tolerated when administered orally (Chandra et al; Clin. Drug. Invest.; 2009, 29(9): 559-575).
However, it was noted that bioavailability of 1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium compounds, for example, 1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium bromide was very low, when administered orally to rats. (Data on file)
Further, phase I clinical studies have also revealed that the oral bioavailability of 1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium chloride is very low (Chandra et al; Clin. Drug. Invest.; 2009, 29(9): 559-575); and high doses (more than 1000 mg bid) are therefore required in order to achieve therapeutically effective response in humans.
It is an aim of certain embodiments of this invention to provide a pharmaceutical formulation of 1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium, its pharmaceutically acceptable salts, salt-cocrystals and co-crystals. It is an aim of certain embodiments to provide formulations which deliver a therapeutically effective amount of 1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium its pharmaceutically acceptable salts, salt-cocrystals and co-crystals orally. It is an aim of certain embodiments to provide formulations which exhibit an increased oral bioavailability of 1-(2-thien-2′-yl-2-oxo-ethyl)-3-(methanesulfonyl hydrazine carbonyl) pyridinium compound relative to prior art formulations. Certain embodiments of the invention achieve some or all of the above aims.